..Collectively, these findings support a model in which epithelial cell TLR signaling upon exposure to microbial stimuli induces active DC sampling of the gut lumen at sites distant from organized lymphoid tissues...

Kaley D WilsonCentre for Drug Research and Development, University of British Columbia, Vancouver, CanadaAdv Drug Deliv Rev 61:233-42. 2009

..Lipid-encapsulation provides a feasible strategy to optimize the immunostimulatory activity and immunotherapeutic efficacy of CpG ODN, thereby allowing their full clinical potential to be realized...

A new paradigm for aptamer therapeutic AS1411 action: uptake by macropinocytosis and its stimulation by a nucleolin-dependent mechanism

..Further, a single set of parameters, derived from 108 oligonucleotide duplexes, adequately describes polymer and oligomer thermodynamics. Empirical salt dependencies are also derived for oligonucleotides and polymers...

PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation

..Thus, PI3K selectively controls type I IFN production by regulating IRF-7 nuclear translocation in human pDCs and could serve as a novel target to inhibit pathogenic type I IFN in autoimmune diseases...

..In the present study, we investigated whether pre-treatment with the synthetic TLR9 ligands 1668-thioate or 1612-thioate modulates the progression of TAC-induced cardiac inflammation and hypertrophy...

..Toll-like receptors (TLRs) have been implicated in myocardial ischemia/reperfusion (I/R) injury. The TLR9 ligand, CpG-ODN has been reported to improve cell survival. We examined effect of CpG-ODN on myocardial I/R injury...

..In preclinical studies, additional aptamers have been described against several cancer targets, such as tenascin-C, the transcription factor signal transducer and activator of transcription 3, and antiapoptotic and Ku proteins...

..We describe a novel strategy to target immunostimulatory oligonucleotides to the initiation site of the immune response while at the same time protecting from an indiscriminate and generalized activation of the immune system...

..This study provides the first experimental evidence that suppressive ODNs inhibit the development of atherosclerosis through inhibition of the STAT1/4 and T-bet pathways, which further modulate the Th1/Th2 balance in vivo...

..Moreover, the use of stable CDODN specific for AP-1 activity in combination with the highly effective HVJ-liposome method provides a novel potential therapeutic strategy for the prevention of restenosis after angioplasty in humans...

..The mutation spectrum of 5-fC was broad, and included targeted (5-fC-->G, 5-fC-->A, and 5-fC-->T) and untargeted mutations. These results suggest that the oxidation of 5-mC results in mutations at and around the modified sites...

The immunobiology and clinical potential of immunostimulatory CpG oligodeoxynucleotides

Haiyan QiDepartment of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USACancer Res 66:11808-16. 2006

..Interestingly, a number of G-quadruplex ODNs (GQ-ODN) derived from nontelomeric sequences also induced ATM/JNK-dependent apoptosis, suggesting a possible common mechanism of tumor cell killing by GQ-ODNs...

..Along with many positive results have come some failures showing the limitations of several therapeutic approaches. This review summarizes these results to provide an overview of the clinical development of CpG ODN...

..This inverted denaturation profile was observed for all G-quartet-forming oligonucleotides studied so far. This technique is very useful in all cases where intramolecular or intermolecular quadruplex formation is suspected...

..Our data add rs41308230 and rs5743844 to the list of functionally important TLR variants and warrant further research into their relevance for infectious disease susceptibility or responsiveness to CpG-ODN-based therapies...

An ISCOM vaccine combined with a TLR9 agonist breaks immune evasion mediated by regulatory T cells in an orthotopic model of pancreatic carcinoma

..The development of a delivery strategy capable of inducing robust anti-tumor responses concurrent with minimal systemic side effects is crucial for the continued progress of potent immunotherapies toward widespread clinical translation...

Lymphoma immunotherapy with CpG oligodeoxynucleotides requires TLR9 either in the host or in the tumor itself

..These results indicate that activation of Ag presentation by cells within the tumor via TLR9 stimulation can be an effective form of immunotherapy. This study forms the basis of an ongoing clinical trial in patients with lymphoma...

..Here we show that this costimulatory effect is sufficient to abrogate suppression by Tregs. These data indicate a previously undefined role for TLR ligands in directly modulating CD4+ T cell responses...

..Our studies reveal a striking and unexpected ability of ODNs to directly activate and polarize T cells, presenting an opportunity to enhance the paradigm for selection of therapeutic ODNs in humans...

..The nature of the cation also has an influence on the adopted structures, with K(+) inducing more parallel multimers than NH4(+) and Na(+). Structural possibilities are discussed for the new quadruplex higher-order assemblies...

Structural basis for the recognition of the FapydG lesion (2,6-diamino-4-hydroxy-5-formamidopyrimidine) by formamidopyrimidine-DNA glycosylase

..These results represent an important basis for the application of CpG-ODN as adjuvants for the formulation of novel vaccines and demonstrate the importance of the pig as an alternative animal model for this approach...

..These studies demonstrate that neutralization of CCL1 can be used as an adjuvant to antitumor immunotherapy, as a means of reversing the immunosuppressive function of Tregs without compromising T cell effector function...

..Together, these results highlight the internal cellular mechanisms that control immune responses and provide a foundation for the development of new mathematical models that are correct at both single-cell and population levels...

..Our synthetic approach should facilitate comprehensive studies of the mechanisms of repair and mutagenesis induced by dG-AAF adducts in DNA and should be of general use for the incorporation of base-labile functionalities into DNA...

..Down-regulation of SSR1, SSR2, and SSR3 will be attempted using antisense oligodeoxyribonucleotides. Functional experiments will examine the effect of somatostatin and stable analogs of somatostatin on ..

..at various guanines within and in the region of codon 12 by using synthetic 15 mer double-stranded oligodeoxyribonucleotides; and e) characterize the DNA repair capabilities of Cosmid 102-transformed excision repair-deficient CHO ..

..of action of natural SNARE-mediated vesicle fusion, this method employs complementary single-stranded oligodeoxyribonucleotides that are anchored to the surfaces of cells and vesicles to facilitate their fusion...

..Question 2A: What mediators promote immune tolerance induced by early life exposure to microbial products? Question 2B: What cells are responsible for immune tolerance induced by early life exposure to microbial products? ..

..Although completion of the second Aim is almost certainly beyond the scope of this two-year developmental research grant, these studies will be continued and extended through an R01 grant application. ..

..Micrometastases, microscopic deposits of tumor that have spread via the bloodstream, are present in many patients with uveal melanoma at diagnosis. This project will test new methods of identifying and inhibiting these deposits. ..

..Two cell lines will be examined for the lesions deemed most representative of the nature of oxidative DNA damage. Three different methods for subjecting cells to oxidative stress will be utilized. ..

..On completion of the program, it is expected that trainees will have a thorough understanding of the various aspects of cancer research, and be able to function as independent cancer researchers in an academic setting. ..

..Third, we shall evaluate how two chemotherapeutic drugs with different modes of action affect detectable DNA lesions, using the FT-IR technology, and attempt to correlate this with their activity in tumor formation. ..

..The third aim is to incorporate the optimal tumor-targeting sequences into antisense, siRNA and immunomodulatory oligonucleotides in order to determine if this leads to superior uptake and activity. ..

..Further elucidation of the molecular mechanisms of Ler action should lead to the development of chemotherapeutic agents directed against EPEC and related E. coli O157 bacteria. [unreadable] [unreadable] [unreadable] [unreadable]..